Young children and infants often respond poorly to immunization with inactivated influenza virus vaccines. Previous studies have suggested that the means and quality of the primary exposure to influenza virus antigens affect the level of antibodies and the probability of protection produced by inactivated influenza virus vaccines. In order to study the effects of route of immunologic priming, serum was collected before and three weeks after administration with a B/Panama/45/90 vaccine from 36 children and infants with defined histories of influenza virus infection and immunization. Thirteen of the children (age 18 +/- 8 months) had neither been previously vaccinated or infected; 16 (age 24 +/- 8 months) had been immunized in the previous year with B/Yamagata/16/88 (a strain closely related to B/Panama/45/90; 7 (age 20 +/- 10 months) had been infected with P/Panama/45/90 as shown by virus isolation (5 children) or seroconversion (2 children). Before immunization, none of the uninfected/unimmunized children had a detectable titer of a hemagglutination inhibition (HI) antibodies (GMT <1:16), but only 50 % of the previously immunized children (GMT <1:16) and all of the previously infected children (GMT = 1:48) had detectable HI antibodies. After immunization the GMT for HI antibodies rose to 1:64 in the unimmunized/uninfected group, to 1:91 for the previously immunized group, and to 1:312 for the previously infected group (p<0.01, one way ANOVA). In addition, there was a significant difference (p<0.05, t-test) in the post immunization GMT for HI antibodies in comparison of the previously immunized children with (post GMT = 1:140) and without (post GMT = 1:54) detectable antibodies before reimmunization. These results indicate that natural infection with an influenza B virus is a more potent means of immunologic priming with longer duration of antibody titers and a greater anamnestic response to subsequent antigenic challenge as compared to administration of inactivated vaccine. The results reinforce the suggestion that a separate strategy of immunization should be developed for young children and infants.